Mastocytosis and COVID19 infection and vaccination: A pediatric series

Introduction: Mastocytosis encompasses a heterogeneous group of diseases characterized by an accumulation of clonal mast cells (MC) in the skin and/or internal organs, and symptoms of MC activation. This MC activation can be elucidated by several factors, including infections or vaccination. Objective(s): We present our experience with COVID infection and vaccination in a series of 133 patients with pediatric mastocytosis. Method(s): Between January 1998 and December 2022, 133 pediatric patients have been referred to our hospital owing to clinically suspected MC disorder, mainly with mastocytosis in the skin. The final diagnoses of mastocytosis were established by the presence of typical skin lesions together with an increase of MC numbers in a biopsy from lesional skin or activating KIT mutations in lesional skin tissue. Serum baseline tryptase and total immunoglobulin E levels were measured, and patients underwent a comprehensive allergy workup to confirm atopic status and history of anaphylaxis. Regarding vaccination, REMA's (Spanish Network on Mastocytosis) protocol was followed. Result(s): 13 patients with COVID infection were identified, of which 25 (56,8%) were female and 0% had symptoms of MC activation. All of them had an asymptomatic or mild course of COVID infection. None of the patients experimented MC activation symptoms during viral illness. Regarding COVID vaccination, all patients received premedication with antihistamine 60 minutes prior vaccination. No one experimented immediate reactions and only one patient (0,75%) referred worsening of MC activation symptoms (baseline pruritus, urtication and brain fog) only after the first doses, recovering without changes in his treatment (oral cromoglycate and antihistamine) in two months. Discussion(s): Although MC have been implicated in the pathogenesis of cytokine storm in COVID19, there is no clinical evidence of SARSCoV- 2-induced MC activation, perhaps related to the fact that bone marrow MC lack angiotensin-converting enzyme 2 receptors.

The role of mast cells and their proteases in lung damage associated with COVID-19.

The new coronavirus infection COVID-19 (Coronavirus Disease 2019) caused by SARS-CoV-2, has posed scientific and public health challenges. The problem of treating COVID-19 still remains, and the pathogenesis of COVID-19 needs to be studied in detail, including the involvement of mast cells (MCs) and their specific proteases. The aim of this study was to characterize the role of mast cell proteases chymase, tryptase, and carboxypeptidase A3 (CPA3) in the lung damage associated with COVID-19. Methods. The study included postmortem lung biopsies from 30 patients who died of severe COVID-19, and biopsies from 9 control group patients. Histological preparations were made and protease profile and degranulation activity of MCs were analyzed. In addition, some demographic, clinical, and laboratory parameters were analyzed. Results. The average number of tryptase-positive MCs without evidence of degranulation and the total number of CPA3-positive MCs were statistically significantly higher in patients with COVID-19, and the number of tryptase-positive and CPA3-positive MCs fragments was lower compared with controls. Negative correlations were established between the numbers of tryptase-positive MCs and red blood cell count. Negative correlations were found between non-granulating tryptase-positive MCs and hemoglobin levels. Positive correlations were noted between tryptase-positive MCs and the leukocytes and eosinophils counts, and negative correlations were noted between the number of CPA3-positive cells and the platelet count. A positive correlation was found between the number of adjoining MCs, as well as fragments of tryptase-positive MCs, and the erythrocyte sedimentation rate (ESR). A negative correlation was also observed between the number of non-degranulated CPA3-positive MCs and the blood level of C-reactive protein. In patients with COVID-19, reduced degranulation activity of tryptase-positive MCs was found along with increased representation of CPA3-positive MCs. Several trends and associations with laboratory test results were noted. The potential involvement of MCs in the development of anemia and thrombocytopenia is considered. Associations were established between tryptase-positive MCs and the peripheral blood counts of leukocytes and eosinophils, as well as ESR. Conclusion. The results obtained are highly contradictory. Since many aspects of the involvement of MCs and their proteases in COVID-19 pathogenesis are still unknown, studies with larger cohorts of patients are needed.Copyright © Budnevsky A.V. et al., 2023.

The role of mast cells and their proteases in lung damage associated with COVID-19.

The new coronavirus infection COVID-19 (Coronavirus Disease 2019) caused by SARS-CoV-2, has posed scientific and public health challenges. The problem of treating COVID-19 still remains, and the pathogenesis of COVID-19 needs to be studied in detail, including the involvement of mast cells (MCs) and their specific proteases. The aim of this study was to characterize the role of mast cell proteases chymase, tryptase, and carboxypeptidase A3 (CPA3) in the lung damage associated with COVID-19. Methods. The study included postmortem lung biopsies from 30 patients who died of severe COVID-19, and biopsies from 9 control group patients. Histological preparations were made and protease profile and degranulation activity of MCs were analyzed. In addition, some demographic, clinical, and laboratory parameters were analyzed. Results. The average number of tryptase-positive MCs without evidence of degranulation and the total number of CPA3-positive MCs were statistically significantly higher in patients with COVID-19, and the number of tryptase-positive and CPA3-positive MCs fragments was lower compared with controls. Negative correlations were established between the numbers of tryptase-positive MCs and red blood cell count. Negative correlations were found between non-granulating tryptase-positive MCs and hemoglobin levels. Positive correlations were noted between tryptase-positive MCs and the leukocytes and eosinophils counts, and negative correlations were noted between the number of CPA3-positive cells and the platelet count. A positive correlation was found between the number of adjoining MCs, as well as fragments of tryptase-positive MCs, and the erythrocyte sedimentation rate (ESR). A negative correlation was also observed between the number of non-degranulated CPA3-positive MCs and the blood level of C-reactive protein. In patients with COVID-19, reduced degranulation activity of tryptase-positive MCs was found along with increased representation of CPA3-positive MCs. Several trends and associations with laboratory test results were noted. The potential involvement of MCs in the development of anemia and thrombocytopenia is considered. Associations were established between tryptase-positive MCs and the peripheral blood counts of leukocytes and eosinophils, as well as ESR. Conclusion. The results obtained are highly contradictory. Since many aspects of the involvement of MCs and their proteases in COVID-19 pathogenesis are still unknown, studies with larger cohorts of patients are needed.Copyright © Budnevsky A.V. et al., 2023.

Systemic reaction triggered by SARS-COV- 2 infection in a patient with chronic autoimmune urticaria

Case report: Chronic urticaria is defined as the presence of urticaria for a period exceeding six weeks. Infections are known as possible triggers for urticaria manifestations, and, as such, SARS-CoV- 2 infection can be recognized as causative. An 8-year- old boy, with a previous history of idiopathic chronic urticaria, came to the Emergency Department for the appearance of generalized urticaria and lips angioedema associated with vomit and shortening of breath normal vital signs by age. Thus, due to the significant reaction, intravenous corticosteroids and antihistamines were promptly administered, with a rapid improvement of symptoms. Since the systemic reaction, the tryptase dosage was performed with the identification of an elevation at the time of the arrival and a complete normalization after the twelfth hour from the beginning of the reaction. Figure 1 shows the kinetic of the tryptase over time. SARS-CoV2 swab was performed before hospitalization and a positive test was identified. To investigate the etiopathogenesis of reaction, the patient was submitted to the extensive clinical, laboratory, and instrumental investigations that revealed only a positive in vitro basophil activation test (BAT) as evidence of functional serum histamine-releasing autoantibodies that are directed against IgE or high-affinity IgE receptors. The viral infection did not need any medication, and the urticaria was resolute in a couple of days. Daily treatment with oral antihistamines was then prescribed, and no further urticarious episodes occurred. A negative SARS-CoV- 2 swab was detected within 12 days of beginning symptoms. Approximately 40% of patients with idiopathic chronic urticaria have circulating antibodies versus IgE epitopes or the IgE receptor, but as it occurs in many autoimmune conditions, the presence of autoantibodies does not necessarily result in a disease phenotype. It is demonstrated that infections can elicit an autoimmune condition, and as our report shows, SARS-CoV2 could explain the reaction observed in our patient. The autoimmune precondition could have been the primer of the systemic reaction, pre-activating the mastocyte degranulation, as the tryptase elevation demonstrated. On the other hand, the SARS-CoV2 virus reducing the ACE2 expression, due to virus endocytosis, could create an imbalance in the RAS system, increasing the bradykinin levels. Bystander activation of pre-activated mastocytes caused by an inflammatory environment could explain the systemic reaction described above.

T HELPER CELL SUBSETS AND RELATED TARGET CELLS IN ACUTE COVID-19.

Current review presents a brief overview of the immune system dysregulation during acute COVID-19 and illustrates the main alterations in peripheral blood CD4+ T-cell (Th) subsets as well as related target cells. Effects of dendritic cell dysfunction induced by SARS-CoV-2 exhibited decreased expression of cell-surface HLA-DR, CCR7 as well as co-stimulatory molecules CD80 and CD86, suggesting reduced antigen presentation, migratory and activation capacities of peripheral blood dendritic cells. SARS-CoV-2-specific Th cells could be detected as early as days 2-4 post-symptom onset, whereas the prolonged lack of SARS-CoV-2-specific Th cells was associated with severe and/or poor COVID-19 outcome. Firstly, in acute COVID-19 the frequency of Th1 cell was comparable with control levels, but several studies have reported about upregulated inhibitory immune checkpoint receptors and exhaustion-associated molecules (TIM3, PD-1, BTLA, TIGIT etc.) on circulating CD8+ T-cells and NK-cells, whereas the macrophage count was increased in bronchoalveolar lavage (BAL) samples. Next, type 2 immune responses are mediated mainly by Th2 cells, and several studies have revealed a skewing towards dominance of Th2 cell subset in peripheral blood samples from patients with acute COVID-19. Furthermore, the decrease of circulating main Th2 target cells - basophiles and eosinophils - were associated with severe COVID-19, whereas the lung tissue was enriched with mast cells and relevant mediators released during degranulation. Moreover, the frequency of peripheral blood Th17 cells was closely linked to COVID-19 severity, so that low level of Th17 cells was observed in patients with severe COVID-19, but in BAL the relative number of Th17 cells as well as the concentrations of relevant effector cytokines were dramatically increased. It was shown that severe COVID-19 patients vs. healthy control had higher relative numbers of neutrophils if compared, and the majority of patients with COVID-19 had increased frequency and absolute number of immature neutrophils with altered ROS production. Finally, the frequency of Tfh cells was decreased during acute COVID-19 infection. Elevated count of activated Tfh were found as well as the alterations in Tfh cell subsets characterized by decreased "regulatory" Tfh1 cell and increased "pro-inflammatory" Tfh2 as well as Tfh17 cell subsets were revealed. Descriptions of peripheral blood B cells during an acute SARS-CoV-2 infection werev reported as relative B cell lymphopenia with decreased frequency of "naive" and memory B cell subsets, as well as increased level of CD27hiCD38hiCD24- plasma cell precursors and atypical CD21low B cells. Thus, the emerging evidence suggests that functional alterations occur in all Th cell subsets being linked with loss-of-functions of main Th cell subsets target cells. Furthermore, recovered individuals could suffer from long-term immune dysregulation and other persistent symptoms lasting for many months even after SARS-CoV-2 elimination, a condition referred to as post-acute COVID-19 syndrome.Copyright © 2022 Saint Petersburg Pasteur Institute. All rights reserved.

Expression of SARS-CoV-2 receptor angiotensin-converting enzyme 2 by activating protein-1 in human mast cells.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection activates mast cells and induces a cytokine storm, leading to severe Coronavirus disease in 2019 (COVID-19). SARS-CoV-2 employs angiotensin-converting enzyme 2 (ACE2) for cell entry. In the present study, the expression of ACE2 and its mechanism in activated mast cells were studied utilizing the human mast cell line, HMC-1 cells and it was elucidated whether dexamethasone used as a treatment for COVID-19 could regulate ACE2 expression. Here we documented for the first time that levels of ACE2 were increased by stimulation of phorbol 12-myristate 13-acetate and A23187 (PMACI) in HMC-1 cells. Increased levels of ACE2 were significantly diminished by treatment with Wortmannin, SP600125, SB203580, PD98059, or SR11302. The expression of ACE2 was most significantly reduced by the activating protein (AP)-1 inhibitor SR11302. PMACI stimulation enhanced the expression of the transcription factor AP-1 for ACE2. In addition, levels of transmembrane protease/serine subfamily member 2 (TMPRSS2) and tryptase were increased in PMACI-stimulated HMC-1 cells. However, dexamethasone significantly lowered levels of ACE2, TMPRSS2, and tryptase generated by PMACI. Treatment with dexamethasone also reduced activation of signaling molecules linked to ACE2 expression. According to these findings, levels of ACE2 were up-regulated through activation of AP-1 in mast cells, suggesting that suppressing ACE2 levels in mast cells would be a therapeutic approach to lessen the harm caused by COVID-19.

Brain Leukocytes as the Potential Therapeutic Target for Post-COVID-19 Brain Fog.

After recovering from the acute phase of coronavirus disease 2019 (COVID-19), many patients struggle with additional symptoms of long COVID during the chronic phase. Among them, the neuropsychiatric manifestations characterized by a short-term memory loss and inability to concentrate are called "brain fog". Recent studies have revealed the involvement of "chronic neuro-inflammation" in the pathogenesis of brain fog following COVID-19 infection. In the COVID-related brain fog, similarly to neurodegenerative disorders caused by neuro-inflammation, brain leukocytes, such as microglia and lymphocytes, are hyperactivated, suggesting the overexpression of delayed rectifier K+-channels (Kv1.3) within the cells. In our previous patch-clamp studies, drugs, such as antihistamines, statins, nonsteroidal anti-inflammatory drugs, antibiotics and anti-hypertensive drugs, suppressed the Kv1.3-channel activity and reduced the production of pro-inflammatory cytokines. Additionally, newer generation antihistamines, antibiotics and corticosteroids strongly stabilize mast cells that directly activate microglia in the brain. Taking such pharmacological properties of these commonly used drugs into account, they may be useful in the treatment of COVID-related brain fog, in which the enhanced innate and adaptive immune responses are responsible for the pathogenesis.

T HELPER CELL SUBSETS AND RELATED TARGET CELLS IN ACUTE COVID-19

Current review presents a brief overview of the immune system dysregulation during acute COVID-19 and illustrates the main alterations in peripheral blood CD4+ T-cell (Th) subsets as well as related target cells. Effects of dendritic cell dysfunction induced by SARS-CoV-2 exhibited decreased expression of cell-surface HLA-DR, CCR7 as well as co-stimulatory molecules CD80 and CD86, suggesting reduced antigen presentation, migratory and activation capacities of peripheral blood dendritic cells. SARS-CoV-2-specific Th cells could be detected as early as days 2–4 post-symptom onset, whereas the prolonged lack of SARS-CoV-2-specific Th cells was associated with severe and/or poor COVID-19 outcome. Firstly, in acute COVID-19 the frequency of Th1 cell was comparable with control levels, but several studies have reported about upregulated inhibitory immune checkpoint receptors and exhaustion-associated molecules (TIM3, PD-1, BTLA, TIGIT etc.) on circulating CD8+ T-cells and NK-cells, whereas the macrophage count was increased in bronchoalveolar lavage (BAL) samples. Next, type 2 immune responses are mediated mainly by Th2 cells, and several studies have revealed a skewing towards dominance of Th2 cell subset in peripheral blood samples from patients with acute COVID-19. Furthermore, the decrease of circulating main Th2 target cells — basophiles and eosinophils — were associated with severe COVID-19, whereas the lung tissue was enriched with mast cells and relevant mediators released during degranulation. Moreover, the frequency of peripheral blood Th17 cells was closely linked to COVID-19 severity, so that low level of Th17 cells was observed in patients with severe COVID-19, but in BAL the relative number of Th17 cells as well as the concentrations of relevant effector cytokines were dramatically increased. It was shown that severe COVID-19 patients vs. healthy control had higher relative numbers of neutrophils if compared, and the majority of patients with COVID-19 had increased frequency and absolute number of immature neutrophils with altered ROS production. Finally, the frequency of Tfh cells was decreased during acute COVID-19 infection. Elevated count of activated Tfh were found as well as the alterations in Tfh cell subsets characterized by decreased "regulatory” Tfh1 cell and increased "pro-inflammatory” Tfh2 as well as Tfh17 cell subsets were revealed. Descriptions of peripheral blood B cells during an acute SARS-CoV-2 infection werev reported as relative B cell lymphopenia with decreased frequency of "naïve” and memory B cell subsets, as well as increased level of CD27hiCD38hiCD24– plasma cell precursors and atypical CD21low B cells. Thus, the emerging evidence suggests that functional alterations occur in all Th cell subsets being linked with loss-of-functions of main Th cell subsets target cells. Furthermore, recovered individuals could suffer from long-term immune dysregulation and other persistent symptoms lasting for many months even after SARS-CoV-2 elimination, a condition referred to as post-acute COVID-19 syndrome.

THE UNEXPLORED POSSIBILITIES, PERCEPTIONS AND ETHICAL IMPLICATIONS OF GENE-EDITING ALLERGIC DISEASE: ENGAGING STAKEHOLDERS IN SOUTH AFRICA

Clinically approved cell and gene therapies are opening up future possibilities to treat and prevent myriad diseases, which may include allergic diseases. In South Africa, this could help alleviate the high disease burden and economic cost of treating such diseases. However, even if viable gene-editing options to treat, cure and prevent allergic diseases become safe, effective and affordable for the South African market within the next few decades, the ethical implications and challenges of perceptions, regulation and oversight to ensure safety and equitable access remain. It would be important for all stakeholders involved, including the public and physicians, clinicians and ethicists on clinical and research ethics committees, to be informed about the possibilities, to engage in discussions with one another and to redress any gaps in knowledge. It would be especially important to determine whether cases for gene-editing aimed at allergy would be applied for therapeutic purposes or for enhancement. Much research and discussion remain to be embarked upon;however, it is imperative that research and engagement are expanded and prioritised.

SARS-CoV-2 vaccine excipients polyethylene glycol and trometamol do not induce mast cell degranulation, in an in vitro model for non-IgE-mediated hypersensitivity.

The development of vaccines against SARS-CoV2 brought about several challenges, including the management of hypersensitivity reactions to these formulations. The search for underlying mechanisms involved in these adverse events initially focused on excipients which may trigger mast cell activation responses via non-IgE pathways: polyethylene glycol and trometamol. We sought to determine whether these components, in their pure form, were capable of stimulating mast cells directly. To test this hypothesis, we used an in vitro model for non-IgE-mediated activation that has previously shown degranulation responses induced via MRGPRX2 with known drug agonists of the receptor. Human LAD2 mast cells were incubated with different concentrations (1, 10, 50 mg/ml) of trometamol and of purified polyethylene glycol/Macrogol (molecular weights: 2,000, 3,350, 4,000, and 6,000). Mast cell degranulation was assessed using a beta-hexosaminidase read-out. Interestingly, degranulation responses for all reagents tested showed no significant differences from those obtained from the negative control (basal degranulation). Receptor-silencing assays were therefore not conducted. In summary, purified PEG and trometamol did not induce mast cell degranulation in this in vitro model for the study of non-IgE mechanisms of drug hypersensitivity, previously shown to be useful in the investigation of MRGPRX2 ligands. Studies using complete vaccine formulations, lipid conjugates, and receptor gene variants are needed to further clarify mechanisms of vaccine hypersensitivity.

Antithrombotics and antihistamine use correlated with increased COVID-19 severity. Antithrombotics and antihistamine use correlated with increased COVID-19 severity

Background: Many medications have been investigated for use in COVID-19 with anticoagulants being recommended as thromboprophylaxis in hospitals. Aim(s): To investigate the effect of prophylactic and prescribed medication on COVID-19 severity. Method(s): An online survey was used to collect patient data relating to medication use prior to COVID-19 diagnosis in recovered patients. Statistics were performed using one-way ANOVA and t-test. This was an international retrospective cohort study approved by the Royal College of Surgeons in Ireland Human Research Ethics Committee. Result(s): 685 participants representing 32 countries responded (age range 18-78 yrs). Antiplatelet and antithrombotic medication was associated with more severe disease, (28% severe vs. 8% mild). Aspirin and ibuprofen use after diagnosis was associated with increased length of disease;(aspirin 54.5 +/- 3.1 days;control 34.8 +/- 2.7 days, (P < 0.05);ibuprofen 54.7 +/- 6.6 days;control 31.8 +/- 2.8 days, P < 0.05). There was an increase in disease severity for patients taking antihistamines both before and after diagnosis (severe 28%, mild 7%;severe 33% mild 10%, respectively). Antihistamine use was associated with longer disease presentation in both groups (before diagnosis: antihistamine 47.5 +/- 7.9 days, control 35.4 +/- 2.7 days, P < 0.01;after diagnosis 51.9 +/- 5.9 days, control 30.8 +/- 2.6 days P < 0.05). Conclusion(s): We anticipated a prophylactic effect of antithrombotic use prior to infection, however, these data do not support this. The association of ibuprofen and aspirin with severe presentation is likely due to their use for patients with more severe COVID-19 or an underlying condition. Antihistamines inhibit the mast cell response which is important for fighting both the initial infection and the subsequent response. These results indicate that antithrombotics should only be used where there is an indicated thrombotic risk and antihistamines should be used with caution. Further work is required in a larger clinical study to confirm these findings.

Temporal model for central sensitization: A hypothesis for mechanism and treatment using systemic manual therapy, a focused review.

The purpose of this focused review is to develop a consolidated hypothesis as to the causes and mechanisms of central sensitization and a related model for a treatment approach using Systemic Manual Therapy (SMT). The key to understanding central sensitization is a firm grasp on structure and function of the Locus-coeruleus noradrenaline system (LC-NA). This system uses an elaborate switching mechanism to control the level and rate of activation of multiple systems. This review evaluates the mechanisms and temporal relationships behind four components: salient stimuli, threat coding, aberrant afferent input, and oxidative stress. The five-stage temporal model for central sensitization includes phasic activation of the LC-NA system, salient stimuli, threat coding of salient stimuli, central sensitization, and neural degeneration. The three components of treatment include temporarily reducing afferent visceral input, shifting humoral inflammatory activity away from the brain and outside the body, and reducing oxidative stress by making oxygenated blood more available around the LC and other stressed areas in the brain. The SMT protocols that could help in reduction of visceral afferent input are GUOU, Barral and LAUG. Protocols that should shift humoral inflammatory activity away from the brain or completely out of the body include UD and DCS. One protocol that can potentially reduce oxidative stress by making oxygenated blood more available around the LC is CCCV. Future research and hypothesis-testing strategies as well as limitations are further discussed.

Mast Cell's Role in Cytokine Release Syndrome and Related Manifestations of COVID-19 Disease.

In this narrative review, firstly, we describe the characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the pathogenesis of its infection in humans. Later, the importance of mast cells in SARS-CoV-2 infection and their role in Coronavirus Disease 2019 (COVID-19) will be discussed. SARS-CoV-2 is a transmissible agent frequently detected in some mammalian species and also in humans. Literature data published in PubMed that covered mast cells' role in cytokine release syndrome and related manifestations of COVID-19 disease were reviewed by the authors independently and collectively. Recommendations for the management of cytokine release syndrome and related manifestations were made by the authors. Mast cells are concentrated in environments where they encounter viruses, bacteria, and toxins, especially in the skin, nasal mucosa, lungs, airways, gastrointestinal tract, and meninges, to prevent their entry into the human body. Once SARS-CoV-2 enters the host, it stimulates one of the mast cells, together with pre-existing innate immune cells that form a defensive barrier in the submucosa of the respiratory tract and nasal cavities against pathogenic microorganisms. The roles of mast cells in SARS-CoV-2-induced hyperinflammation and cytokine storms have recently been one of the hot topics in the literature. Physicians should keep in mind the mast cells' role in cytokine release syndrome and related manifestations of COVID-19 disease. Mast cell-targeting therapies (e.g., H1 and H2 receptor antagonists) can reduce the severity and course of the disease when used after complications associated with COVID-19 are suspected or seen.

Pathophysiology of Post-COVID syndromes: a new perspective.

Most COVID-19 patients recovered with low mortality; however, some patients experienced long-term symptoms described as "long-COVID" or "Post-COVID syndrome" (PCS). Patients may have persisting symptoms for weeks after acute SARS-CoV-2 infection, including dyspnea, fatigue, myalgia, insomnia, cognitive and olfactory disorders. These symptoms may last for months in some patients. PCS may progress in association with the development of mast cell activation syndrome (MCAS), which is a distinct kind of mast cell activation disorder, characterized by hyper-activation of mast cells with inappropriate and excessive release of chemical mediators. COVID-19 survivors, mainly women, and patients with persistent severe fatigue for 10 weeks after recovery with a history of neuropsychiatric disorders are more prone to develop PCS. High D-dimer levels and blood urea nitrogen were observed to be risk factors associated with pulmonary dysfunction in COVID-19 survivors 3 months post-hospital discharge with the development of PCS. PCS has systemic manifestations that resolve with time with no further complications. However, the final outcomes of PCS are chiefly unknown. Persistence of inflammatory reactions, autoimmune mimicry, and reactivation of pathogens together with host microbiome alterations may contribute to the development of PCS. The deregulated release of inflammatory mediators in MCAS produces extraordinary symptoms in patients with PCS. The development of MCAS during the course of SARS-CoV-2 infection is correlated to COVID-19 severity and the development of PCS. Therefore, MCAS is treated by antihistamines, inhibition of synthesis of mediators, inhibition of mediator release, and inhibition of degranulation of mast cells.

ORGANIZING PNEUMONIA WITH FOREIGN BODY REACTION AS A RESULT OF SODIUM HYDROXIDE AND AMMONIUM SALT VAPOR EXPOSURE

SESSION TITLE: Occupational and Environmental Lung Disease Cases SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 12:25 pm - 01:25 pm INTRODUCTION: Sodium hydroxide and ammonium salt vapor exposure are known to cause epithelial necrosis of the tracheobronchial tree, but no pathologic descriptions exist of subsequent inflammatory pneumonitis. CASE PRESENTATION: A 56-year-old man presented to the outpatient clinic with 2 months of progressive scant hemoptysis and dyspnea on exertion. He had a mild smoking history, a history of longstanding stable UC, and had a history significant only for recently performing multiple weeks of cleaning work on a large, enclosed HVAC system with chemicals containing sodium hydroxide and ammonium. He wore no respiratory protection at work. CXR was significant for streaky bilateral lower lobe opacities and CT Chest revealed bilateral basilar ground-glass opacities with a small left pneumothorax. His PFT demonstrated mild restriction with a diffusion defect. Infiltrates persisted after treatment with levofloxacin. A broad autoimmune panel was normal. Bronchoscopy with cryobiopsy showed organizing pneumonia with foreign body reaction. BAL showed primarily mast cells and no organisms were found. Prednisone at 60mg daily with Bactrim prophylaxis and a subsequent prolonged wean was initiated with marked improvement. DISCUSSION: Industrial HVAC cleaning agents are widely used with the proliferation of HVAC systems in the post-COVID world. Other examples exist of prolonged cleaning product use and lung function decline (Svanes et al). Our case report hypothesizes a link between inhalational exposure to sodium hydroxide and ammonium salts with organizing pneumonia with foreign body features, a previously unknown effect. Prednisone led to improvement. CONCLUSIONS: High suspicion for occult pneumonitis should exist when patients present with prolonged exposure to cleaning/noxious chemical vapors exist. Respiratory protection should be emphasized as a public health policy to prevent lung damage among any type of cleaner use including high-skilled (HVAC) cleaners. Reference #1: Advenier, A., & Grandmaison, G. (2022). PULMONARY ACUTE LESIONS AFTER CAUSTIC EXPOSURE. Retrieved 31 March 2022, from https://www.lungdiseasesjournal.com/articles/pulmonary-acute-lesions-after-caustic-exposure.html Reference #2: Svanes, Ø., Bertelsen, R. J., Lygre, S., Carsin, A. E., Antó, J. M., Forsberg, B., García-García, J. M., Gullón, J. A., Heinrich, J., Holm, M., Kogevinas, M., Urrutia, I., Leynaert, B., Moratalla, J. M., Le Moual, N., Lytras, T., Norbäck, D., Nowak, D., Olivieri, M., Pin, I., … Svanes, C. (2018). Cleaning at Home and at Work in Relation to Lung Function Decline and Airway Obstruction. American journal of respiratory and critical care medicine, 197(9), 1157–1163. https://doi.org/10.1164/rccm.201706-1311OC Reference #3: Gorguner, M., & Akgun, M. (2010). Acute inhalation injury. The Eurasian journal of medicine, 42(1), 28–35. https://doi.org/10.5152/eajm.2010.09 DISCLOSURES: no disclosure on file for Ai-Yui Maria Tan;No relevant relationships by Sudha Misra No relevant relationships by Amrik Ray

NOT THE VACCINE, BUT ANAPHYLAXIS TO THE COVID-19 VIRUS ITSELF

SESSION TITLE: Poster Cases in Asthma and Allergy SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: Anaphylaxis is an acute, potentially life-threatening, systemic allergic reaction that presents as a multitude of manifestations after exposure to an allergen. It is rare to have an anaphylactic reaction to the SARS-Cov-2 vaccine, however, we present a patient who had a prolonged anaphylactic reaction to the SARS-CoV-2 virus itself. CASE PRESENTATION: A 23-year-old female with past medical history of chronic idiopathic urticaria and dermatographism presented with fatigue, rash, rhinitis, and lip swelling in the setting of being COVID-19 positive. She had received two doses of the Pfizer-BioNTech COVID-19 vaccine nine months prior without any adverse affects. During the SARS-CoV-2 Omicron variant surge, the patient was exposed to a family member who had contracted COVID-19 infection. Two days prior to presentation, she started having a diffuse rash throughout her body. In the Emergency Department, she was given IM epinephrine x2, IV Solu-Medrol and IV Benadryl with temporary improvement in her symptoms. She developed hypotension that required initiation of a continuous epinephrine infusion and was admitted to the Medical Intensive Care Unit. Each time the epinephrine was held, generalized urticaria recurred and she would become hypotensive with her systolic blood pressure decreasing below 80 mmHg. The urticaria completely resolved and her blood pressure improved when the epinephrine infusion was restarted. The patient was treated with remdesivir, Solu-Medrol, loratadine, and famotidine. She was able to be weaned off the epinephrine infusion over the course of four days. Immunological workup was unremarkable apart from elevation of IL-10 on her cytokine panel. DISCUSSION: The symptoms and syndromes associated with COVID-19 infection remain diverse and while urticaria has been a documented manifestation of the virus, it is uncommon (1). There is a single case report of an anaphylactic reaction in response to COVID-19 (2). Given our patient's symptoms were temporally related to the COVID-19 infection, we believe the SARS-COV-2 virus was the trigger. She did not have any other exposure during this time. This case is unique in that the virus not only triggered the urticaria, but that her symptoms persisted for four days. After receiving antiviral therapy plus steroids and antihistamines, her symptoms finally resolved. The SARS-COV-2 virus itself is primarily attacked by immune cells, including mast cells, which release an array of proinflammatory cytokines (3). We postulate that in our patient, her history of chronic urticaria predisposed her to an exaggerated inflammatory response. CONCLUSIONS: SARS-CoV-2 has clinically presented itself in a multitude of ways across many disciplines. In a patient with a history of urticaria, prolonged anaphylactic symptoms can be triggered by the virus itself. Reference #1: Adeliño R., Andrés-Cordón J.F., De la Cruz Martínez C.A. Acute urticaria with angioedema in the setting of coronavirus disease 2019. J Allergy Clin Immunol Pract. 2020;8(7):2386–2387. Reference #2: Alvarez-Perea A, Baeza ML. Anaphylactic shock following the diagnosis of coronavirus disease 2019. Ann Allergy Asthma Immunol. 2020;125(4):477-478. Reference #3: Kritas SK, Ronconi G, Caraffa A, Gallenga CE, Ross R, Conti P. Mast cells contribute to coronavirus-induced inflammation: new anti-inflammatory strategy. J Biol Regul Homeost Agents. 2020 January-February,;34(1):9-14. DISCLOSURES: No relevant relationships by Brianne Navetta-Modrov No relevant relationships by Azzam Paroya Speaker/Speaker's Bureau relationship with Bayer Please note: current Added 03/30/2022 by Paul Strachan, value=Honoraria Speaker/Speaker's Bureau relationship with United Therapeutics Please note: more than 5 years Added 03/30/2022 by Paul Strachan, value=Honoraria Speaker/Speaker's Bureau relationship with Gilead Please note: $1001 - $5000 by Paul Strachan, value=Honoraria Removed 03/30/2022 by Pau Strachan Speaker/Speaker's Bureau relationship with Genentech Please note: $5001 - $20000 by Paul Strachan, value=Honoraria Removed 03/30/2022 by Paul Strachan Speaker/Speaker's Bureau relationship with Boehringer Ingelhein Please note: More than 5 years Added 03/30/2022 by Paul Strachan, value=Honoraria Stock Ownership relationship with Pfizer Please note: Purchased in 2000-2002 Added 03/30/2022 by Paul Strachan, value=nothing, I purchased stock Speaker/Speaker's Bureau relationship with Portola Please note: $1001 - $5000 by Paul Strachan, value=Honoraria Removed 03/30/2022 by Paul Strachan Stock Ownership relationship with Portola Please note: $5001 - $20000 by Paul Strachan, value=nothing, I purchased stock Removed 03/30/2022 by Paul Strachan Stock Ownership relationship with La Jolla Pharmaceuticals Please note: Purchased a few years back Added 03/30/2022 by Paul Strachan, value=nothing, I purchased stock Stock Ownership relationship with Seatle Genetics Please note: Purchased more than 5 years ago Added 03/30/2022 by Paul Strachan, value=nothing, I purchased stock PI relationship with United Therapeutics Please note: Current Added 03/30/2022 by Paul Strachan, value=Grant/Research Support PI relationship with Actelion/Janssen Please note: Current Added 03/30/2022 by Paul Strachan, value=Grant/Research Support PI for clinicial trial relationship with Roche Please note: Current Added 03/30/2022 by Paul Strachan, value=Grant/Research PI for clinicial trial relationship with Bellerophon Please note: Current Added 03/30/2022 by Paul Strachan, value=Grant/Research Support Speaker/Speaker's Bureau relationship with Actelion/Janssen Please note: Current Added 03/30/2022 by Paul Strachan, value=Honoraria

Defining mast cell differentiation and heterogeneity through single-cell transcriptomics analysis.

Mast cells (MCs) are widely recognized as central effector cells during type 2 inflammatory reactions and thought to also play a role in innate immune responses, wound healing, and potentially cancer. Circulating progenitor cells mature to MCs in peripheral tissues, where they exhibit phenotypic and functional heterogeneity. This diversity likely originates from differences in MC development imprinted by microenvironmental signals. The advent of single-cell transcriptomics reveals MC diversity beyond differences in proteases that were classically used to identify MC phenotypes. Here, we provide an overview of the current knowledge on MC progenitor differentiation and characteristics, and MC heterogeneity seen in health versus disease, that are drastically advanced through single-cell profiling technologies. This powerful approach can provide detailed cellular maps of tissues to decipher the complex cellular functions and interactions that may lead to identifying candidate factors to target in therapies.

Anaphylaxis to COVID-19 Vaccines

Severe allergic reactions to vaccines are rare and occur approximately once per million administrations. The most severe form of an immediate reaction is anaphylaxis, usually IgE-mediated, and may cause death. Immediate reactions with features of anaphylaxis have been reported after immunization with COVID-19 vaccines, mainly after the mRNA vaccines. The reported incidence of 2.5 to 4.7 events per million administrations of mRNA vaccines is higher than reported rates of anaphylaxis (1 per million) with other vaccines. Anaphylaxis after injection of other COVID-19 vaccines has also been reported, although to a lesser extent. Many individuals who experienced possible anaphylaxis to COVID-19 vaccines had a history of allergy to various other allergens. While a history of anaphylaxis to other substances (e.g., foods, drugs, insect stings) is not a contraindication to vaccination, it is recommended that such individuals remain for 30 minutes of observation after receiving the injection, rather than the 15 minutes recommended for all other vaccine recipients. History of anaphylaxis after receiving other vaccines or the first dose of COVID-19 vaccine is a contraindication of COVID-19 vaccine injection. As with any vaccine, all vaccination sites should be equipped with the medications (epinephrine) and staff required to treat possible anaphylactic reactions. Mast cell-mediated reactions may involve various combinations of up to 40 potential symptoms and signs, which typically begin within minutes to an hour of vaccination, but can rarely be delayed beyond this time frame. It is also essential to understand that some other reactions to vaccines can mimic anaphylaxis, including vasovagal reactions and anxiety-related symptoms.

Mast cell activation syndrome and the link with long COVID.

Mast cells are innate immune cells found in connective tissues throughout the body, most prevalent at tissue-environment interfaces. They possess multiple cell-surface receptors which react to various stimuli and, after activation, release many mediators including histamine, heparin, cytokines, prostaglandins, leukotrienes and proteases. In mast cell activation syndrome, excessive amounts of inflammatory mediators are released in response to triggers such as foods, fragrances, stress, exercise, medications or temperature changes. Diagnostic markers may be difficult to assess because of their rapid degradation; these include urinary N-methyl histamine, urinary prostaglandins D2, DM and F2α and serum tryptase (which is stable) in the UK. Self-management techniques, medications and avoiding triggers may improve quality of life. Treatments include mast cell mediator blockers, mast cell stabilisers and anti-inflammatory agents. 'Long COVID' describes post-COVID-19 syndrome when symptoms persist for more than 12 weeks after initial infection with no alternative diagnosis. Both mast cell activation syndrome and long COVID cause multiple symptoms. It is theorised that COVID-19 infection could lead to exaggeration of existing undiagnosed mast cell activation syndrome, or could activate normal mast cells owing to the persistence of viral particles. Other similarities include the relapse-remission cycle and improvements with similar treatments. Importantly, however, aside from mast cell disorders, long COVID could potentially be attributed to several other conditions.